Drug Discovery & Development
Neal G. Simon, Ph.D. Professor Department of Biological Sciences Drug Discovery & Development: Bench, Bedside, & Beyond
I. Background
II. The R&D Landscape
III. Innovation and Transformation
IV. The Preclinical Development Process
V. Case Study: A Novel Antidepressant
VI. Ethical Issues: Money, Data, & Politics Disclaimer
“Those who have knowledge, don’t predict. Those who predict, don’t have knowledge.” Lao Tzu, 6th Century BC Chinese Poet Serendipity or Good Science: Building Opportunity
Hoffman Osterloh I. Background Drug Development Process: Stages
US FDA Drug Development Process: Phases
Biopharmaceutical Drug Development: Attrition
Drug FDA Large Scale Discovery Pre-Clinical Clinical Trials Review Manufacturing / Phase IV
Phase I Phase III 20-100 1000-5000 Volunteers Volunteers
10,000 1 FDA Com- 250 Compounds 5 Compounds Approved pounds Drug IND Submitted Submitted NDA Phase II 100-500 Volunteers
5 years 1.5 years 6 years 2 years 2 years
Quelle: Burrell Report Biotechnology Industry 2006 II. The Research & Development Landscape New Chemical Entities: R&D Cost Model
Discovery: $263/$824 million Development: $632/1054 million
Paul et al (2010). Nature Rev Drug Discovery Annual Private & Public R&D Spending Research & Development Spending: Return on Investment
Saltzmann (2009). Feeding the Pipeline III. Innovation & Transformation
Innovation Models and Transformation
Hu et al (2007)
Antidepressants: Me Too Drugs
1986 Fluvoxamine (Luvox; Solvay) SSRI
1987 Fluoxetine (Prozac; Lilly) SSRI
1992 Sertraline (Zoloft; Pfizer) SSRI/NRI
1993 Venlafaxine (Effexor; Wyeth) SSRI/NRI
1996 Buproprion (Wellbutrin; Wyeth) SNRI/DRI
2002 Escitalopram (Lexapro; Forrest) SSRI
2004 Duloxetine (Cymbalta; Lilly) SSRI/NRI
2008 Desvenlafaxine (Pristiq; Wyeth/Pfizer) SNRI
2011 Vilazidone (Vybrid; Forest Labs) SSRI/5HT1a
Personalized Medicine (sort of)
Discovery & Preclinical Development
IV. Discovery & Development Preclinical Development
Lead Selection and Drug Candidate Preclinical Drug
Optimization (iterative) Confirmation Characterization RegulatorySubmission to FDA
Efficacy Assessment: Does it work?
ADME Profiling: How can it be delivered and what does the body do?
Toxicology/Safety Pharmacology Assessment: Is it safe?
Pharmaceutics: Is the manufacture viable and controllable?
Adapted from TetraQ Stage 1: Lead Selection and Optimization
Essential Pharmaceutics
• Structural Characterization • Impurity Identification • Solubility assessment • Prototype formulation • Stability testing
Screening Efficacy Early Toxicology Early ADME
• In silico profiling • Off target screen • In vitro models • Develop simple • In vitro cytotoxicity • In vivo models analytical method • Preliminary AMES • Other • Measure membrane • hERG binding permeability • Plasma Stability
Adapted from TetraQ Stage 2: Drug Candidate Confirmation
Data from Lead Optimization Stage
Preliminary CMC “Benchmark” in Preliminary (Chemistry, ADME Profiling Manufacture and vivo Models Toxicology Control)
• Optimized • Formulation for analytical • Maximum GLP Toxicology method tolerated dose • Stability testing • In vivo models development (MTD) of active • Validated • Basic pharma- • Repeat Dose ingredient models cokinetics (PK) (non-GLP) • Detailed • Models in other & Oral • Preliminary physicochemical disease areas Bioavailability Cardiovascular characterization • Determine Safety • Impurity metabolism of Pharmacology analysis drug
Adapted from TetraQ Stage 3: Preclinical Drug Characteristics
Data from Prior Stages
Detailed Preclinical Comprehensive GLP Toxicology CMC ADME Package
• analytical method • acute study • ICH Stability development • subchronic repeat Testing • Comprehensive dose study • ICH impurity Pharmacokinetics • Genotoxicity analysis • GLP TK Battery •Develop prototype • Comprehensive • Safety clinical formulation identification of Pharmacology metabolites
Regulatory Submission to FDA or Presentation to Pharmaceutical Company
Adapted from TetraQ
V. Case Study: Agomelatine
Major Depression: Symptoms
Anhedonia
Blunted Affect
Disturbed Sleep
Weight Gain/Weight Loss
Compromised Social Interactions The Scream Fear Circuits: Core Components
Hippocampus and Amygdala
Anterior & Rostral Cingulate Cortex
Insular Cortex
Edvard Munch, 1893 Shin & Liberzon (2010) Hypothalamic-Pituitary-Adrenal Axis
Biological Sciences Hypothalamic-Pituitary-Adrenal Axis
Key Considerations
Regulatory Peptides . CRF . AVP
Feedback Regulation . Glucocorticoids
Biorhythm Disturbance . Sleep .Temperature . Cardiac . HPA axis
Biological Sciences Major Depression & Biorhythms
Alterations in circadian rhythms of behavior, sleep, core temperature and the secretion of cortisol and other hormones
Blunted amplitude of daily rhythms and poor responsiveness to environmental entraining stimuli.
Circadian desynchronization may also be triggered by disorganization of the suprachiasmatic nucleus
Circadian disturbances may be provoked by an abnormal pineal output of melatonin, a key synchronizer of biological rhythms and sleep
Depression is associated with an altered diurnal rhythm of melatonin output, including a blunted night time surge
Administration of melatonin itself is ineffective in major depression
Re-coordination of biological rhythms by recruitment of melatonergic mechanisms may be a therapeutically relevant strategy for improving depressed states. Melatonin, Circadian Rhythms, & Agomelatine
Agomelatine: Mechanism of Action
Discovery, Development, Characterization, & Approval of Agomelatine
Key Pharmacological Observations
V. Ethics Neurontin
PFIZER LOSES A ROUND OVER MARKETING OF NEURONTIN By BLOOMBERG NEWS A judge in Boston upheld a jury decision that Pfizer illegally promoted Neurontin for unapproved uses. Pfizer said it would appeal. January 29, 2011
EXPERTS CONCLUDE PFIZER MANIPULATED STUDIES By STEPHANIE SAUL The drug maker manipulated the publication of studies to bolster use of its epilepsy drug Neurontin, according to expert witnesses in a lawsuit against the company. Oct 8, 2008
PFIZER TO PAY $430 MILLION OVER PROMOTING DRUG TO DOCTORS By GARDINER HARRIS Pfizer pleads guilty and agrees to pay $430 million to resolve criminal and civil charges that it paid doctors to prescribe epilepsy drug Neurontin to patients with ailments that drug was not federally approved to treat. May 14, 2004 Politics, Medicine, & Responsibility
http://www.youtube.com/watch?v=pPZn9mRQlq4 Serendipity or Good Science: Building Opportunity
Hoffman Osterhloh Thank you for your time and attention